Red Blood Cell-based Biomaterials For Biomedical Application

In recent years,cancer immunotherapy has achieved significant clinical therapeutic outcomes and has received widespread attention.However,low immune response rate and immune-related side effects limit its further application.A variety of novel biomaterials and strategies have been reported to deliver therapeutics for immunotherapy.Among them,cell and cell-derived biomaterials,such as red blood cells,platelets,cellderived vehicle and exosomes have been extensively studied for drug delivery.Therefore,how to use cell vectors to construct efficient immune regulation strategies to improve the response rate of immunotherapy and reduce side effects is one of the important issues in this thesis.Red blood cells are the most abundant type of blood cells that exist in blood vessels.Compared with drug delivery systems based on synthetic materials,natural red blood cells have many advantages such as easily-obtained,high drug loading capacity,excellent biocompatibility,etc.In recent years,red blood cell-based drug delivery vehicles have been considered as ideal candidates and have received more and more attention.The purpose of this doctoral dissertation is to use red blood cells which are provided with high biological safety to construct a new drug carrier for the immunotherapy of diseases,including cancer and inflammation.The main research contents and results of the full text are summarized as follows:Chapter 1:First,give a brief overview of drug delivery systems.Then,introduce drug delivery systems based on red blood cells,red blood cell-targeting or loading strategies,and red blood cell-derived drug delivery systems.Finally,clarify the basis and specific research content of this doctoral dissertation.Chapter 2:Tumor vaccines show great potential in the prevention and treatment of cancer.In the work of this chapter,we designed and manufactured an implantable erythrocyte gel scaffold made of autologous blood,which can be used to construct an enhanced tumor vaccine.The RBC-gel is a fibrin gel network formed by the cascade hemagglutination process triggered by the blood in vitro,which captures a large number of erythrocytes.The erythrocyte gel is gently dried in a vacuum to induce aging of the erythrocytes.After implantation,the damaged and aged red blood cells inside the red blood cell gel can attract and recruit a large number of immune cells,thereby forming an"immune niche" in situ.Furthermore,using red blood cell gel to load tumor-associated antigens and adjuvants to prepare tumor vaccines based on red blood cell gel can stimulate the immune niche to form a highly activated state,inducing infiltrating initial immune cells to transform into anti-tumor specific immune cells,thereby inducing powerful anticancer immune response.The combination of red blood cell gel vaccine and immune checkpoint blockade therapy can effectively inhibit tumor growth in B16F10 and 4T1 tumor models.A personalized cancer vaccine is constructed by mixing blood from cancer patients with immunomodulators outside the body.Based on this,the red blood cell gel vaccine constructed in this chapter has the prospect of clinical transformation in the future.Chapter 3:At present,the treatment of large-scale bone defects still faces many difficulties and challenges.Here,we designed and developed a red blood cell gel delivery system loaded with BMP-2 protein to promote bone repair.The erythrocyte gel delivery platform,as a natural biological material,can be engineered from autologous blood.Once implanted in a large area of bone defect,it can be used as a carrier for local delivery of BMP-2 drugs.On the other hand,red blood cell gel can recruit a large number of macrophages and adjust their polarization state at different stages to regulate bone immunology.In addition,based on the deep red color of the red blood cell gel,slight local warming induced by the irradiation of the laser further accelerates the repair and regeneration of bone.We find that the immune niche in the microenvironment of bone defect can be adjusted by implanting red blood cell gel and gentle photothermal treatment.In mouse and rat bone defect models,the newly formed bones after treatment cover almost 95%of the skull defect area.Chapter 4:Chronic inflammation is one of the key causes of aging.Reversing chronic inflammation provides great possibilities for anti-aging.In the work of this chapter,we try to use nanobiotechnology to treat age-related chronic inflammation.Red blood cell-derived nanovesicles prepared by using red blood cells with high biological safety and compatibility can efficiently target immune cells in the mouse liver and spleen.Besides,erythrocyte-derived nanovesicles loaded with NMN can significantly revive the vitality of immune cells in the body and significantly reduce the level of inflammation in mice with chronic inflammation.This treatment strategy offers the potential to reverse age-related inflammation and fight to age.In summary,this thesis reports biomaterials based on red blood cells for the immunotherapy of diseases,including preparing red blood cell gel vaccines for anti-tumor treatment,and red blood cell gel with photothermal effects for bone repair treatment,and preparing erythrocyte-derived nanovesicles targeted to immunological cells for anti-aging treatment.The biomaterial strategies established in this article have a high degree of safety,superior biocompatibility,and biodegradability,providing a theoretical basis for the development of new biomaterials,and has the possibility of future clinical translation.